芳香環上取代基修飾對 Wulff 型硼酸衍生物的酸性及其與二醇結合之研究

Abstract

硼酸是一種具有廣泛應用的分子，像是它們可以在有機合成中作為 Suzuki-Miyaura 偶聯反應的試劑，在材料科學中用於合成感測器或共價有機框架 (COFs)，以及在醫學中作為各種藥物被使用。其中苯基硼酸 (PBA) 因為能夠與環境中的順式二醇或是多元醇形成可逆的共價鍵所以具有檢測多種醣類的能力而受到關注。 本篇論文使用 benzoboroxole 這種類型的硼酸，由於其雜環硼原子上存在游離羥基以及相對較強的路易士酸性中心，因此 benzoboroxole 化合物通常表現出比相應的 PBA 更高的酸性，預期可以在生理方面提高其對於目標的選擇性或結合力。 我們合成一系列 benzoboroxole 的衍生物，並且測定該化合物的 pKa 值，驗證取代基的推拉電子效應對酸性的影響，並且發現具有硝基修飾的 benzoboroxole 衍生物具有比目前文獻中最低的 pKa 值。再來運用茜素紅 S (Alizarin Red S, ARS) 與硼酸締結後產生螢光的現象，經由數學推導得到與ARS的結合常數 (KARS)，再進一步計算與不同二醇在各種 pH 環境中的結合常數 (Keq)，探討這一系列硼酸的反應性以及在生理情況下的應用性。由實驗結果可以觀察到連接鏈的存在會增加硼缺電子的能力，修飾上硝基的化合物在生理條件下與各種醣類表現出比其他硼酸更優異的結合能力。我們運用分子探針與唾液酸以及不同的目標分子進行締結測試，結果表明含有硝基的 benzoboroxole 衍生物對於唾液酸的親和力於酸性條件中是最好的，這與二醇自身的結構相關，以及電荷形式也會對結合造成影響。對於目標分子而言，皆表現出良好的結合效果。 本研究通過降低了硼酸的 pKa，達成在生理條件中有更好的結合效果，並且在各方面硝基硼酸分子探針都展現出與各式目標二醇良好的能力。

Boronic acids are molecules with wide range of applications, such as being used as reagents in Suzuki-Miyaura coupling reactions in organic synthesis, synthesizing sensors or covalent organic frameworks (COFs) in material science, and drugs in medicine. Among them, phenylboronic acid (PBA) has attracted attention due to its ability to form reversible covalent bonds with cis-diols or polyols in the environment, making it effective in probing various carbohydrates. In this study, we use the type of boronic acid called benzoboroxoles. Due to the presence free hydroxyl groups and relatively strong Lewis acid centers on the heterocyclic boron atom, benzoboroxole usually show higher acidity than PBA. This is expected to improve their selectivity or binding affinity towards the target physiologically. We synthesized a series of benzoboroxole derivatives and measured their pKa values to verify the influence of electro-donating and electro-withdrawing substituents on their acidity. We also found that Nitro-modified benzoboroxole derivatives has the lowest pKa value compare to the current literature. With the fluorescence property of Alizarin Red S (ARS) bonded with boronic acid, we were able to calculate the binding constants with different diols (Keq) in different pH conditions to explore the reactivity and the applicability of these series of boronic acids in physiological conditions.The results showed that the presence of linkers enhance the electron-deficient of boron atom. Benzoboroxole modified with strong electro-withdrawing groups exhibited an excellent binding capability with various carbohydrates under physiological conditions compared to other boronic acids. We conducted binding tests using molecular probes with sialic acid and other target molecules. The results revealed that Nitro-modified benzoboroxole derivatives had the best affinity for sialic acid under acidic conditions, which is related to the geometry of diols and the formal charge. For all the target molecules, they exhibited an outstanding performance of binding affinity. This study successfully enhanced the binding performance under physiological conditions by reducing the pKa of boronic acid. Nitro-modified molecular probes exhibited a fantastic probing capability for various diols.